ABSTRACT Ticks are obligate blood-feeding arthropods that transmit numerous pathogens to both humans and livestock. Lyme disease, which is caused by transmission of the spirochete Borrelia burgdorferi by the deer tick Ixodes scapularis, is responsible for over 95% of vector-borne disease cases in the United States. Despite the importance of ticks as disease vectors, elucidating the molecular basis for tick?pathogen relationships has lagged due to our incomplete understanding of tick innate immunity. We recently identified an antibacterial enzyme in I. scapularis that was co-opted from bacteria through horizontal gene transfer. This domesticated amidase effector (dae2) gene encodes an active, bacteriolytic cell wall hydrolase that is enriched in the gut and salivary glands of ticks. We found that Dae2 affords previously uncharacterized antibacterial activity to the innate immune system of ticks and propose to investigate its role in shaping tick?microbe interactions and vector competence for the Lyme disease pathogen B. burgdorferi. This work will advance our fundamental understanding of how ticks have evolved to selectively control bacteria they transmit and potentially offer new avenues for blocking the tick-borne cycle of infection for an important human pathogen.